{"entity":{"id":"paper-topalian-anti-pd1-nejm-2012","kind":"paper","name":"Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer","aka":[],"tldr":"Nivolumab shrank tumours in roughly a fifth to a quarter of patients with three different advanced cancers, with responses that lasted more than a year and a hint that PD-L1 on the tumour predicted benefit.","summary":"This phase 1 dose-escalation and expansion study treated 296 patients with advanced melanoma, non-small-cell lung cancer, renal cell carcinoma, castration-resistant prostate cancer or colorectal cancer with the anti-PD-1 antibody BMS-936558 (nivolumab) at 0.1 to 10 mg/kg every two weeks. Objective responses occurred in 28% of melanoma, 18% of NSCLC and 27% of renal cancer patients, but none in prostate or colorectal cancer; of 31 responders followed for a year or more, 20 had responses lasting at least a year. Grade 3-4 drug-related adverse events occurred in 14%, and there were three deaths from pneumonitis. In 42 patients with tumour PD-L1 staining, 9 of 25 PD-L1-positive tumours responded versus none of 17 PD-L1-negative tumours. A companion paper (Brahmer et al.) reported similar activity for an anti-PD-L1 antibody.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1200690"},{"label":"Companion anti-PD-L1 paper (Brahmer 2012)","url":"https://doi.org/10.1056/NEJMoa1200694"}],"tags":[],"related":["paper-hodi-ipilimumab-melanoma-nejm-2010","pd1-checkpoint","lung-cancer-evidence-roadmap","paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020"],"cancers":["melanoma","nsclc","lung-cancer"],"sections":[],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["nivolumab","pembrolizumab","atezolizumab"],"companies":["bms"],"institutions":[],"pathways":[],"terms":["irae","orr"],"trials":[],"people":["suzanne-topalian","julie-brahmer","drew-pardoll","f-stephen-hodi"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1200690","authors":"Topalian SL, Hodi FS, Brahmer JR, et al.","paperType":"translational","findings":["296 patients across five tumour types; nivolumab 0.1-10 mg/kg every 2 weeks.","Objective response: melanoma 28%, NSCLC 18% (including squamous and non-squamous), renal cell carcinoma 27%; none in prostate or colorectal cancer.","Responses durable: 20 of 31 responders with a year or more of follow-up had responses lasting at least 1 year.","Grade 3-4 drug-related adverse events 14%; 3 deaths from pneumonitis.","PD-L1 expression: 9 of 25 PD-L1-positive tumours responded vs 0 of 17 PD-L1-negative."],"whatItMeans":"This study is why PD-1 inhibitors were developed across cancers rather than in melanoma alone: unexpected activity in lung cancer, historically thought immune-resistant, changed drug development priorities industry-wide. It also introduced PD-L1 immunohistochemistry as a candidate biomarker and pneumonitis as a signature toxicity. Within five years PD-1 blockade was approved in more than ten cancers.","caveats":["Phase 1 with heterogeneous doses and small tumour cohorts; response rates are imprecise.","PD-L1 analysis was on 42 patients with archival tissue; the biomarker later proved imperfect.","No colorectal responses masked the later dMMR story (the one responder in an earlier study was dMMR).","Survival was not assessed."],"changedPractice":true,"participants":296},"route":"/key-papers/paper-topalian-anti-pd1-nejm-2012/","neighbours":{"paper":[{"id":"paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020","kind":"paper","name":"Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC","route":"/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/"},{"id":"paper-hodi-ipilimumab-melanoma-nejm-2010","kind":"paper","name":"Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma","route":"/key-papers/paper-hodi-ipilimumab-melanoma-nejm-2010/"},{"id":"paper-pardoll-immune-checkpoint-blockade-nrc-2012","kind":"paper","name":"Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy","route":"/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"}],"cancer":[{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"atezolizumab","kind":"drug","name":"Atezolizumab","route":"/drugs/atezolizumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"term":[{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"},{"id":"orr","kind":"term","name":"Objective response rate (ORR)","route":"/terms/orr/"}],"person":[{"id":"drew-pardoll","kind":"person","name":"Drew M. Pardoll","route":"/people/drew-pardoll/"},{"id":"f-stephen-hodi","kind":"person","name":"F. Stephen Hodi","route":"/people/f-stephen-hodi/"},{"id":"gordon-freeman","kind":"person","name":"Gordon J. Freeman","route":"/people/gordon-freeman/"},{"id":"julie-brahmer","kind":"person","name":"Julie R. Brahmer","route":"/people/julie-brahmer/"},{"id":"lieping-chen","kind":"person","name":"Lieping Chen","route":"/people/lieping-chen/"},{"id":"suzanne-topalian","kind":"person","name":"Suzanne L. Topalian","route":"/people/suzanne-topalian/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"idea":[{"id":"idea-tr1-extended-interval-checkpoint-dosing","kind":"idea","name":"Extended-interval immunotherapy: give checkpoint inhibitors every 8-12 weeks once stable","route":"/ideas/idea-tr1-extended-interval-checkpoint-dosing/"},{"id":"idea-chronotherapy-immunotherapy","kind":"idea","name":"Give immunotherapy in the morning","route":"/ideas/idea-chronotherapy-immunotherapy/"},{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/"},{"id":"idea-microbiome-io-fmt","kind":"idea","name":"Microbiome transplant as a routine immunotherapy adjunct","route":"/ideas/idea-microbiome-io-fmt/"},{"id":"idea-tr1-immunotherapy-stop-trials","kind":"idea","name":"Randomised trials of stopping immunotherapy after one year versus continuing","route":"/ideas/idea-tr1-immunotherapy-stop-trials/"}]}}